At a first glance, this young lady has presented with a confusing jumble of signs and symptoms involving multiple systems. However, a careful and systematic analysis reveals three distinct clusters of clinical findings:
- Neurological manifestations: dysarthria, tremors, and an abnormal gait
- Psychiatric symptoms: depression and anxiety. - Hepatobiliary features: jaundice
The presence of neurological and psychiatric symptoms in combination with liver disease should always raise suspicion of Wilson's Disease (WD), an autosomal recessive disorder of copper metabolism with a broad spectrum of presentation.
If this is excluded, other di erentials which one would need to consider include hemochromatosis, chronic viral hepatitis, cirrhosis, and perhaps, systemic lupus erythematosus (SLE).
Slit lamp examination is a rapid and inexpensive next step; this demonstrates Kayser-Fleischer (KF) rings, indicating copper deposition in the cornea.
Assessment of serum ceruloplasmin levels should follow; the value <10 mg/dL seen here combined with the presence of KF rings is su icient to establish the presence of WD.
As per American Academy for Study of Liver Disease (AASLD) recommendations, all individuals with WD should undergo neuroimaging prior to the initiation of treatment; here, this reveals multiple depositions in the basal ganglia, along with a characteristic imaging finding - the "face of the giant panda".
Prompt and appropriate treatment of WD o en results in significant symptomatic improvement, and can also halt disease progression. Chelation therapy plays a key role, with penicillamine being the agent most o en used. Zinc therapy should also be commenced, as this will reduce copper absorption in the gut.
As WD is transmitted in an autosomal recessive fashion, screening of close family members is also essential. Note that corticosteroids have no therapeutic role here.
Discussion Wilson's Disease (WD) is an autosomal recessive disorder of copper metabolism which manifests as a combination of neuropsychiatric symptoms and cirrhotic liver disease.
The genetic basis is a defect in the ATP7B gene, which is located on chromosome 13 and codes for copper-transporting P-type ATPase protein.
This protein is primarily expressed in hepatocytes, where it is involved in the transmembrane transport of copper ions; it is responsible both for the incorporation of copper into apo-ceruloplasmin to form ceruloplasmin (a copper-binding protein) and for the elimination of copper via bile.
Thus, the ultimate outcome is the progressive accumulation of copper in the liver, and its eventual release into the bloodstream and subsequent deposition in various other organs (particularly the brain, kidneys, and cornea).
Therefore, the mode of clinical presentation may fall into one of the following broad categories: hepatic, neurological, psychiatric, or other. The first two types predominate, possibly because of preferential copper deposition in these organs. Symptoms can commence at any age, but typically begin between 5 and 35 years; only 3% of patients diagnosed beyond the fourth decade of life.
Hepatic involvement mostly occurs in the first and second decades of life, in the form of asymptomatic hepatomegaly, jaundice, or frank liver failure.
Neurological manifestations usually occur in the twenties, or sometimes earlier. These include tremors, incoordination, dystonia, Parkinsonism, choreiform movements, gait abnormalities, dysphonia, dysphagia, dysarthria, or anarthria.
Behavioral and psychiatric manifestations include depression, paranoia, hallucinations, sexual exhibitionism, and frank psychosis. They most o en occur in conjunction with neurological disease.
Up to 10% of patients demonstrate 'other' findings, including endocrinopathies such as hyperparathyroidism, menstrual irregularities, and infertility; renal involvement in the form of nephrolithiasis or aminoaciduria; cardiac disease such as cardiomyopathy or arrhythmias; skeletal disorders such as arthritis or premature osteoporosis; and a coombs-negative hemolytic anemia.
Kayser-Fleischer (KF) rings are the clinical hallmark of the condition and are due to copper deposition in Descemet's membrane of the cornea. They are present in over 95% patients with neuropsychiatric symptoms, but in only 50% to 60% of those with hepatic involvement alone.
Note that KF rings are not pathognomonic for WD, as they are found in other diseases that lead to copper deposition.
Given the broad spectrum of presentation, WD can be extremely tricky to diagnose, especially in the early stages. Thus, the European Association for Study of the Liver (EASL) recommends considering it in the di erential diagnosis of any liver disease of unknown origin, until proven otherwise.
Furthermore, the condition should also be suspected in patients of any age presenting with unexplained neurological and/or psychiatric symptoms, with or without liver disease; and in the first-degree relatives of individuals already diagnosed.
Clasically, WD has been recognized by the clinical triad of cirrhosis, neuropsychiatric manifestations, and KF rings; more recently, the presence of a serum ceruloplasmin <10 mg/dL, and KF rings has been considered diagnostic.
That said, almost half of patients who initially exhibit hepatic involvement fail to meet the aforementioned criteria; in such individuals the Leipzig score which takes into account both clinical features (neurologic symptoms and KF rings) and biochemical parameters (Serum ceruloplasmin, presence of coombs-negative hemolytic anemia, urinary copper, liver copper, mutation analysis) can be used to arrive at a diagnosis.
Note also that imaging techniques such as MRI and CT may reveal abnormalities in the basal ganglia, especially in patients presenting with neurological features.
In this respect, a rare but almost pathognomonic MRI finding is the ‘face of the giant panda’ sign; this is formed by a combination of high-intensity signals in the tegmentum, normal intensity signals in the red nuclei and lateral pars reticulata, and low-intensity signals in the superior colliculus.
Despite the low risk (0.5%) of disease in o spring, many practitioners also justify the use of screening tests for the ATP7B mutation, given the potentially devastating course of the illness. If present, each a ected family member should receive appropriate counseling.
The goal of treatment is to reduce the level of copper in the body by either facilitating urinary excretion or reducing intestinal absorption.
The chelating agent D-penicillamine play a key role in this respect; however, adverse e ects, including neurological deterioration, are intolerable in around 30% of patients. Trientine, also a chelating agent, is an alternative in these individuals.
Zinc therapy is also of benefit; this induces an endogenous chelating agent, metallothionein, which binds copper and promotes its fecal excretion. Note that zinc should not be used as monotherapy.
Routine monitoring should proceed in parallel with treatment. This includes liver biochemistries, blood counts, international normalization ratio (INR), and serum copper and ceruloplasmin levels. Orthotopic liver transplantation (OLT) is the only definitive therapy available; it is frequently necessary for patients who present with acute liver failure (~5%), or decompensated cirrhosis that fails to respond to medical treatment.
Untreated Wilson's disease is universally fatal; the majority of deaths are a result of hepatic involvement, with only a minority being due to neurological complications.
Successful medical treatment can reverse behavioral and cognitive features within 1 to 2 years. Hepatic functions may also normalize in patients who present with either no, or compensated, cirrhosis.
Take home messages
1. Wilson's disease (WD) has a varied spectrum of presentation; it should always be considered in individuals with unexpected liver abnormalities or movement disorders of uncertain etiology. 2. Kayser-Fleischer (KF) rings are the characteristic sign of WD, although their absence does not preclude the diagnosis. 3. Treatment is lifelong; early detection and management results in a significantly improved prognosis.
References 1. MEDICI V., ROSSARO L., STURNIOLO G.C.. Wilson's disease—A practical approach to diagnosis, treatment and follow-up. Digestive and Liver Disease [online] 2007 July, 39(7):601-609 [viewed 01 May 2015] Available from: doi:10.1016/j.dld.2006.12.095 2. SCHILSKY MICHAEL L.. Wilson's disease: Clinical manifestations, diagnosis, and treatment. Clinical Liver Disease [online] December, 3(5):104-107 [viewed 01 May 2015] Available from: doi:10.1002/cld.349 3. HANAğASı FIGEN, HANAğASı HAşMET A. Wilson's Hastalığı. Tnd [online] 2013 December, 19(4):122-127 [viewed 01 May 2015] Available from: doi:10.4274/Tnd.60566 4. WIGGELINKHUIZEN M., TILANUS M. E. C., BOLLEN C. W., HOUWEN R. H. J.. Systematic review: clinical e icacy of chelator agents and zinc in the initial treatment of Wilson's disease. [online] 2009 May, 29(9):947-958 [viewed 01 May 2015] Available from: doi:10.1111/j.1365-2036.2009.03959.x 5. EASL Clinical Practice Guidelines: Wilson's's disease. Journal of Hepatology [online] 2012 March, 56(3):671-685 [viewed 01 May 2015] Available from: doi:10.1016/j.jhep.2011.11.007 6. ROBERTS EVE A., SCHILSKY MICHAEL L.. Diagnosis and treatment of Wilson's disease: An update. Hepatology [online] December, 47(6):2089-2111 [viewed 01 May 2015] Available from: doi:10.1002/hep.22261 7. ROBERTS E. A practice guideline on Wilson's disease. Hepatology [online] 2003 June, 37(6):1475-1492 [viewed 01 May 2015] Available from: doi:10.1053/jhep.2003.50252 8. FERENCI PETER, CACA KAREL, LOUDIANOS GEORGIOS, MIELI-VERGANI GEORGINA, TANNER STUART, STERNLIEB IRMIN, SCHILSKY MICHAEL, COX DIANE, BERR FRIEDER. Diagnosis and phenotypic classification of Wilson's disease1. Liver Int [online] 2003 June, 23(3):139-142 [viewed 01 May 2015] Available from: doi:10.1034/j.1600-0676.2003.00824.x
